EPCO-26. INTEGRATIVE MULTI-OMICS IDENTIFIES CONVERGING DEVELOPMENTAL ORIGINS OF DISTINCT MEDULLOBLASTOMA SUBGROUPS. (12th November 2021)

• Record Type: Journal Article
• Authors: Smith, Kyle; Bihannic, Laure; Gudenas, Brian; Gao, Qingsong; Haldipur, Parthiv; Hovestadt, Volker; Iskusnykh, Igor; Chizhikov, Viktor; Deng, Mei; Glass, Ian; Robinson, Giles; Orr, Brent; Patay, Zoltan; Aldinger, Kimberly; Millen, Kathleen; Northcott, Paul
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi7
• Page End: vi7
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.025
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Understanding the interplay between normal development and tumorigenesis, including the identification and characterization of lineage-specific origins of MB, is a fundamental challenge in the field. Recent studies have highlighted novel associations between biologically distinct MB subgroups and diverse murine cerebellar lineages via cross-species single-cell transcriptomics. Specifically, Group 4-MB correlated with the unipolar brush cell lineage and Group 3-MB resembled Nestin+ stem cells of the early cerebellum. However, these analyses were hampered by low resolution due to the sparsity of pertinent cerebellar cell types and the cross-species nature of the approach. Herein, we profoundly expand the depth of these rare developmental populations in the murine cerebellum using a combination of lineage tracing and integrative multi-omics. Isolation and enrichment of spatially and temporally unique developmental trajectories of key rhombic lip-derived glutamatergic lineages provided an enhanced reference for mapping MB subgroups based on molecular overlap, especially for poorly defined Group 3- and Group 4-MB. Further comparisons to a novel single-cell atlas of the human fetal cerebellum, companioned with laser-capture microdissected transcriptional and epigenetic datasets, reinforced developmental insights extracted from the mouse. Characterization of compartment-specific transcriptional programs and co-expression networks identified in the human upper rhombic lip implicated convergent cellular correlates of Group 3- and Group 4-MB, suggestive of a common developmental link. Together, our results strongly implicate developmental lineages of the upper rhombic lip as the probable origins of poorly defined Group 3- and Group 4-MB. These important findings will shape future efforts to accurately model the biological heterogeneity underlying these subgroups and provide unprecedented opportunities to explore their cellular and mechanistic basis.